International Journal of Pharmacy and Pharmaceutical Sciences

Vol 2, Suppl 2, 2010

ReviewArticle

AREVIEW:NEUROPHARMACOLOGICALSCREENINGTECHNIQUESFORPHARMACEUTICALS

YOGESHCHANDYADAV1*,AVIJEETJAIN2,LOKESHDEB3
1*

Department of Pharmacy, Sumandeep Vidyapeeth University, Pipariya Vadodara (G.P.) -391760, India, 2 Dr. H.S.G.University, Sagar 470003
(M.P), India, 3 Institute of Bioresources and Sustainable Development Goverment of India - Takyelpat, Imphal, Manipur -795001
Email:yogeshycypcology2@gmail.com
Received:17Jan2010,RevisedandAccepted01Feb2010

ABSTRACT
Thisreviewpresentsvariousmodelstoscreenvarioustraditionaldrugsandmoderndrugsforneurologicaleffects.Thisbringsacompilationmake
easytogothroughthevariousmodelsatsametimeandmakeit easytoscreenthe drugs.Itrevealsprinciple,apparatusandprocedureofthese
models.Thisscreeningmodelcanbeusetostudyofmemoryenhancing,Anxiolytic,Antidepressantandanticonvulsantactivity.
Keyword:Scopolamine;Elevatedplusmaze;ShuttleBoxAvoidance;Muricidebehaviour;Pentylenetetrazole(PTZ);ElectroShock(MES);

INTRODUCTION
The Central nervous system (CNS) comprising of the brain and
spinal cord process information with the help of chemical
messenger
viz.
neurotransmitter,
neuromodulators,
neuroregulators, neuromediators and neurotropic factor which act
via specific mechanism to mediate neurotransmission,
neurotransmitter viz., nor adrenaline, adrenaline, dopamine,
GammaAminoButyricAcid(GABA),glutamate,acetylcholine, 5
hydroxytryptamine (5HT), peptides viz. endorphins, seretonin,
glycogen and vasoactive intestinal polypeptides(VIP) etc and
neuromodulator viz. prostaglandins (PGs), purines and
neuropeptidesinteractwiththeirrecognitionsitesi.e.receptorand
regulatethefunctionofCNS(1).
According to the world health report (WHO 2001) approximately
450million people suffer from a metal or behavioral disorder, yet
onlyasmallminorityofthemreceiveeventhemostbasictreatment
thisamountto12.3%oftheglobalburdenofdiseaseandwillriseto
15%by2020(2).

social activities. Dementia is of several types and it invariably

involves impairment of memory. The most common cause of
dementia is Alzheimer's disease, which is a progressive
neurodegenerative disorder associated with loss of neurons in
distinct brain areas. The central cholinergic pathways play a
prominent role in learning and memory processes (5). Centrally
acting antimuscarinic drugs (e.g. scopolamine) impair learning and
memory both in animals(6)and human beings (7).Epidemiological
studiesofIndianpopulationrevealthatdementiaislargelyahidden
problem (8). Prevalence rates for dementia increase exponentially
with advancing age (9&10). Since allopathic system of medicine is
yet to provide a radical cure, it is worthwhile to look for new
directions, which would minimize the memory loss seen in elderly
patients.Variouslaboratorymodelsfortestinglearningandmemory
are
1.

Scopolamine induced amnesia (Interoceptive Behaviour

Model).

2.

Diazepaminducedamnesia(InteroceptiveBehaviourModel).

Drugactinginthecentralnervoussystemwereamongthefirsttobe
discovered by the primitive human and are still the most widely
used group of pharmacological agents. The CNS acting drugs are
invaluable therapeutically, because they can produce specific
physiological and psychological effects from the vast array of
materialmedicaoftheindigenoussystemsomanyplantshavebeen
reportedtohaveactivityagainstCNSdisordersandthusactasvery
usefulremediesforthealleviationofhumansuffering(3).

3.

Elevatedplusmaze(ExteroceptiveBehaviourModel).

4.

Shuttleboxavoidance(Twowayshuttlebox)

5.

Passiveavoidanceparadigm(Exteroceptivebehaviormodels)

In the search of new therapeutic product for the treatment of

neurological disorder medicinal plant research worldwide has
progressed constantly, demonstrating the pharmacological
effectivenessofdifferentplantspeciesinavarietyofanimalmodels
(2).

The administration of the antimuscarinic agent scopolamine to

young human volunteers produces transientmemory deficits (11).
Analogously,scopolamine has been shown to impair
memoryretention when given to mice shortly before training in a
dark avoidance task (12,13,&14). The ability of a range of different
cholinergic agonist drugs to reverse the amnesic effects of
scopolamine is now well documented in animals and human
volunteers. However, the neuropathology of dementia of the
Alzheimertypeisnotconfinedtothecholinergicsystem(15).

Many classical animal models of preliminary pharmacological tests

of activities on CNS which provide information about action upon
psychomotorperformance,motorbehaviourandneurotoxicity.The
depressionactivitygivesanindicationoftheleveloftheexcitability
of the CNS and this decrease may be related to sedation resulting
fromdepressionofCNS(4).
This review presents various models to screen various traditional
drugs and modern drugs for neurological effects. This brings a
compilation make easy to go through the various models at same
time and make it easy to screen the drugs. It reveals principle,
apparatusandprocedureofthesemodels.
NEUROPHARMACOLOGICALSCREENINGTECHNIQUES
Memoryenhancingactivity
Dementia is a mental disorder characterized by loss of intellectual
abilitysufficientlysevereastointerferewithone'soccupationalor
10

Scopolamineinducedamnesiainmice
Principle

Procedure
The administration of the antimuscarinic agent scopolamine to
young human volunteers produces transient memory deficits.
Analogously, scopolamine has been shown to impair memory
retention when given to mice shortly before training in a dark
avoidancetask.
Thescopolaminetestisperformedingroupsof10maleNMRImice
weighing2632ginaonetrial,passiveavoidanceparadigm.Five
minute after i.p. Administration of 3 mg/kg scopolamine
hydrobromide, each mouse is individually placed in the bright part
ofatwochambered(brightanddark)apparatusfortraining.
IntJPharmacyPharmSci

Afterabrieforientationperiod,themouseenterstheseconddarker
chamber. Once inside the second chamber door is closed which
preventsthemousefromescaping,anda1mA,1seefootshockis
applied through the grid floor. The mouse is then returned to the
homecage.Twentyfourhourslater,testingisperformedbyplacing
the animal again in the bright chamber. Latency in entering the
second darker chamber. The latency in entering the second darker
chamber within a 5 min. test session is measured electronically.
Whereasuntreatedcontrolanimalsenterthedarkerchamberinthe
second trial with latency about of 250 see, treatment with
scopolaminereducesthelatencyto50sec.Thetestcompoundsare
administered90minbeforetraining.Aprolongedlatencyindicates
thattheanimalremembersthatithasbeenpunishedand,therefore,
doesavoidthedarkerchamber.
Usingvarious doses latenciesafter treatmentwith test compounds
are expressed as percentage of latencies in mice treated with
scopolamineonly.Insomecasesstraightdosesresponsecurvescan
be established whereas with other drugs inverse Ushaped dose
responsesareobserved(14).

apparatus is placed in a dimly lit room with a masking noise

background(whitnoise)of60dB.Theanimalisallowedtoexplore
theapparatusfor5minuteswiththeconnectingdooropenandthe
compartmentlightsswitchedoff.Theguillotinedooristhenclosed.
20 sec the light is switched on in the compartments containing the
animal and the door is opened. A tone (CS) is presented and 5 sec
laterthefloorshockisappliedinthisilluminatedcompartmentand
continued until the animal escapes to the dark side of the
compartment; the connecting door is close and the shock
discontinued.Afterinvariableintertrial(ITI;3090Sec)thelightis
switchedoninpreviousdarkcompartment,thedoorisopenedand
animalisrequiredtocrosstoanotherside.Thetrainingiscontinued
untilanimalreachescriticalof9avoidancesin10consecutivetrials.
Retentionistestedatdifferentintervalaftertheoriginaltrainingby
theretainingtheanimaltosamecriterionagain.
The animal need to reach the safe on both days is measured. In
additionthenumbererror(notreachingthesafearea)isrecorded.

Elevatedplusmaze(exteroceptivebehaviourmodel)

Thetaskisratherdifficultduetolackofpermanentsafearealackof
simple instrumental response, presences of variable aversive
gradientandincreasedweightofemotionfactor.

Principle

Passiveavoidanceparadigm(exteroceptivebehaviormodel)

Outofmanypossibilitiestomodifymazetestse.g.watermaze(16),
theYmace,theradialmaze(17),andtheelevatedplusmaze(18&
19)havefoundacceptanceinmanylaboratories.Thetesthasbeen
proposed for selective identification of anxiolytic and anxiogenic
drugs. Anxiolytic compounds, by decreasing anxiety, increase the
open arm exploration time; anxiogenic compounds have the
oppositeeffect.

Principle

Procedure

Procedure

Elevatedplusmazeservedtoevaluatelearningandmemoryinmice.
The procedure, technique and end point for testing learning and
memory is followed as per parameters described by the
investigatorsworkingintheareaofneuropsychopharmacology

Passive avoidance behaviour based on the negative reinforcement

used to examine the long term memory (21 & 22). The apparatus
considered ofa box(27cm x27cmx 27cm)havingthreevales of
woodandonewallofPlexiglas,featuringagridfloor(3mmstainless
steel rods set 8mm apart), with a wood platform(10cm x 7cm x
1.7cm ), in center of grid floor. The box is illuminated with 15 W
bulbs during experimental period. Electric shock (15V AC) is
delivered to the grid floor. Training is carried out in two similar
sessions. Each mouse gently placed on wood platform set in center
gridfloor.When themousestepped downplaceallits pawsonthe
gridfloor,shockisdeliveredto15secandstepdownlatency(SDL)
is recorded. SDL is defined as time taken by mouse to sleep down
from wood platform to grid floor all its paws on grid floor. Animal
showingtheSDLinrang(215sec)duringfirsttestareusedforthe
secondsessionandtheretentiontest.Thesecondsessioncarriedout
at90minafterthefirsttest.Whenanimalsteppeddownforperiod
of60secretentionistestedafter24hinthesimilarmanner, except
electricshockisnotappliedtogridfloor.Eachmouseagainplaceon
theplatformandtheSDLisrecorded,withtheuppercutoftimeof
300sec.

The apparatus consisted of two open arms (16cm x 5cm) and two
closed arms (16cm x 5cm x12cm). The arms extended from a
centralplatfrom(5cmx5cm)andthemazeiselevatedtoaheightof
25cmofthefloor.Onthefirstday,suchmouseisplacedattheend
of an open arm, facing way from the central platform. Transfer
latency(TL)istakenbymousewithallitsfourlegstomoveintoone
of enclosed arms .TL is recorded on the first day. If the animal did
notenteredarmswithin90sec.Itisgentlypushedintooneoftwo
enclosed arms and TL is recorded at 90 s. then three consecutive
mice are allowed to explore the maze for another 10s and then
returned to its home cage. Retention of this learned task is
examined24Hafterthefirstdaytrial.Anotherlaboratorymodelviz.
passive avoidance apparatus was employed to substantiate the
findingsandovercomethelimitationsoftheelevatedplusmaze.
Shuttleboxavoidance(TwoWayShuttleBox)
Principle
Compared to runway avoidance, shuttle box avoidance (twoway
shuttlebox)isamoredifficulttask.Sincetheanimalisnothandled
betweentrials,theshuttleboxcanbeeasilyautomated(20).
Procedure
Compared to runway avoidance, shuttle box avoidance (twoway
shuttlebox)isamoredifficulttask.Sincetheanimalisnothandled
betweentrials,theshuttleboxcanbeeasilyautomated.
Rats of both sex are used and maintained under standard
conditions.Theapparatususedconsistofarectangularbox50 x15
cm2with40cmhighmetalwalls,andanelectrifiablegridfloor.The
box is divided by a wall with a manually or solenoid operated
guillotine door (10 x 10 cm2) into two 25 x 15 cm2 compartments.
Eachcompartmentscanbeilluminatedbya20Wbulbmountedin
the hinged Plexiglas lids. A fixed resistance shock source with an
automatic switch (0.5 sec on 1.5 sec off) is used. Simple
programming equipment provides for automatic delivery of the
command stimulus (CS) and the unconditioned stimulus (US). The
11

One of the most common animal tests in memory research is the

inhibition to imitate activities or learned habits. The term passive
avoidanceisusuallyemployedtodescribeexperimentsinwhichthe
animal learns to avoid a noxious event by suppressing a particular
behaviour.

AnxiolyticActivity
Principle
Theanimalmodelisconsideredoneofmostwidelyvalidatedtestsof
assaying sedative and anxiolytic substances such as
benzodiazepines.Thetestdruginducedanxiolyticeffectbeginningat
lower doses employed. An increase of most important variables of
EPMtestwasfoundasfollow;thepercentageoftimeofmicespend
on the open arms as well as the percentage of entries in the dark
arms.Theanxiolyticeffectisalsoevidencedthroughlightand dark
test. As with the EPM test, this model is useful for modeling of
anxiety. The low dose dependent effect could be attributed to
biologicalvariability,aswellaschemicalcomplexityofthetestdrug.
Variousmodelofantianxiolytictestingare(23&24)
1.

Elevatedplusmazemodel(EPM).

2.

Forcedswimmingtest(FST).

3.

Lightdarktest(LDT)

4.

Openfieldtest(OFT)
IntJPharmacyPharmSci

Elevatedplusmaze(EPM)
This has widely validated to measure anxiety to rodents. This
apparatus is made of Plexiglas and consisted to two open arms
(30cmx5cm)with30cmwalls.Thearmsextendedfromthecentral
platform (5cm x5cm). This wall is elevated 38.5cm from the room
floor.
The each animal is placed at the center of maze, facing one of the
enclosed arms. Number of entries and time spend in enclosed and
openisrecordedfor5mintest..Entryanarmisdefinedasanimal
placing all four paws onto the arm. All tests are tapped by using a
videocamera.Aftereachtest,themazeiscarefullycleanedupwith
wettissuepaper(10%ethanolsolution).
ForcingswimmingTest(FST)
The FST is most widely used pharmacological in vivo model
assessing anti depressant activity. The development of immobility
whenmiceareplacedininescapablecylinderfillwithwaterreflects
cessation of persistent escape directed behaviour (23). The
apparatus consist of clear Plexiglas cylinder (20cm height x 12 cm
diameter) filled to a15cm depth within the water (25) in the pre
test session, every animal is placed individually into cylinder for
15 min. 24h prior to the 5min swimming test the test drug and
distilled water are administered three time, immediately after 15
minpretest,18and1hpriortotheswimmingtest.Duringthe test
session a trained observer registered the immobility time,
considered to be when the mouse made no further attempts to
escape,apartfromthemovementsnecessarytokeepitsheadabove
the water. It is suggested that the immobility reflected a state of
loweredmoodinwhichtheanimalshadgivenuphopeoffindingan
exitandhadresignedthemselvestotheexperimentssituation.
Lightdarktest(LDT)
The apparatus consists of a Plexiglas box with two compartments
(20x20cm)oneofwhichisilluminatedwithawhitelightwhilethe
other remained dark. Each animal is placed at the centered of the
illuminatedcompartments;facingoneofthedarkplaces,aswellas
thenumberofentriesineachspaceisrecordedfor5min
Openfieldtest(OFT)
Open field test area is made of acrylic transparent walls and black
floor (30cmx 30cmx15cm) divided into nine square of equal area.
Theopenfieldisusedtoevaluatetheexploratoryactivityofanimal
(25). The observed parameters are the number of square crossed
(withthefourpaws)andnumberofrearing.
Antidepressantactivity
Antidepressant activity was indicated the mood elevating due to
various mechanism of the antidepressant drugs, such as inhibition
of the enzyme of monoamine oxidase, inhibition of reuptake
bioamines and enhancement of the concentration of 5HT e) ct
.Lateron,inhibitionofreuptakeofbioamineswasfoundtobemain
mechanismofactiontodowenregulationofreceptor(26).Several
linesofpreclinicalandclinicalevidenceindicatesthatenhancement
of 5HT mediated neurotransmission might underline the
therapeutic effect of most of the antidepressant This behavioural
effectverysimilartothatfoundbyotherauthoraftertreatingmice
withclassicalantidepressantdrugsasIMI(27).
Variousmodelsforantidepresentactivitiesareasfollows.
1.

DespairSwimTest

2.

Learnedhelplessnesstest

3.

Muricidebehaviourinrats

DespairswimTest
Principle
Behavioural despair was proposed as a model to test for
antidepressantactivity.Itwassuggestedthatmiceorratsforcedto
swim in a restricted space from which they cannot escape are
inducedtoacharacteristicbehaviourofimmobility.Thisbehaviour
12

reflectsastateofdespairwhichcanreducebyseveralagents which
aretherapeuticallyeffectiveinhumandepression(28&29).
Procedure
Male SpragueDawley rats weighing 160180 g are used. They are
broughttothelaboratoryatleastonedaybeforetheexperimentand
are housed separately in Makrolon cages with free access to food
and water. Naive rats are individually forced to swim inside a
vertical. Plexiglas cylinder (height: 40 cm; diameter: 18 cm,
containing 15 cm of water maintained at 25 C). Rats placed in the
cylinders for the first time are initially highly active, vigorously
swimmingincircles,tryingtoclimbthewallordivingtothebottom.
After23minactivitybeginstosubsideandtobeinterspersedwith
phases ofimmobilityorfloatingofincreasinglength.After56min
immobility reaches a plateau where the rats remain immobile for
approximately 80% of the time. After 15 min in the water the rats
areremovedandallowedtodryinaheatedenclosure(32C)before
being returned to their home cages. They are again placed in the
cylinder24hlaterandthetotaldurationofimmobilityismeasured
duringa5mintest.Floatingbehaviourduringthis5minperiodhas
beenfoundtobereproducibleindifferentgroupsofrats.Ananimal
is judged to be immobile whenever it remains floating passively in
the water in a slightly hunched but upright position, its nose just
abovethesurface.Testdrugsorstandardareadministeredonehour
prior to testing. Since experiments with the standard drug
(imipramine)showedthatinjections1,5and24hpriorthetestgave
the most stable results in reducing floating these times are chosen
fortheexperiment.
Learnedhelplessnessinrats
Principle
Animals exposed to inescapable and unavoidable electric in one
situation later fail to escape shock in a different situation when
escape is possible (30). This phenomenon was evaluated as a
potential animal model of depression (31 & 32).On day 19th of the
investigationratsaresubjectedtofootshock(60scrambledshocks
,15sduration,0.8mA,everymin)inatwocompartmentjumpingbox
with the escape door to the unelectrified adjoining compartment
closed .The exercise continued for one h .On day 21, 48 hour
afterwards the rates are subjected to avoidance training using the
same apparatus but keeping the escape route to the unelectrified
chamberopen.Duringthisavoidancetraining,theratsareplacedin
theelectrifiedchamberallowedtoacclimatizefor5minbeforebeing
subjected to 30 avoidance trials with an intertribal interval of 30s.
Duringthefirst3softrialsabuzzerstimulusispresentedfollowed
byelectroshockthroughthegridfloorforthenext3s.Theavoidance
response, characterized by escape to the adjoining safe chamber
during conditioned stimulus, is noted. Failure to escape during
unconditionedstimuluswithin15sisassessedasescapefailure.
MuricidebehaviorinRats
Principle
Horovitz et al. described a selective inhibition of mousekilling
behaviour in rats by antidepressants (33). The test can be used to
evaluateantidepressantssuchastricyclicandMAOinhibitors.
Procedure
Male SpragueDawley rats (300350 g) are isolated for 6 weeks in
individualcages.Theyhaveaccesstofoodandwateradlibitum.One
mouseisplacedintotheratscage.About10to30%ofratskillthe
mouse by biting the animal through the cervical cord. Only rats
consistentlykillingmicewithin5minafterpresentationareusedfor
thetest.Themiceareremoved15to45saftertheyhavebeenkilled
inordertopreventtheratsfromeatingthem.Drugsareinjectedi.p.
to the rats before the test. Mice are presented 30, 60 and 120 min
afterdrugadministration.
AnticonvulsantActivity
Different type of epilepsies that is grandmal, petitmal or
psychomotor type can be studied in laboratory animals. Various
modelofAntconvulsiontestare(34).
IntJPharmacyPharmSci

1.

Pentylenetetrazole(PTZ)SeizerTest

2.

ElectroShock(MES)InducedConvulsions

3.

OtherTest

4.

Toxicityprofile

5.

Effectonpentobarbitalinducedsleepingtime

6.

Motilitytest

7.

Amphetaminetoxicitytest

Pentylenetetrazole(PTZ)SeizerTest
Principle
This assay has been used primarily to evaluate antiepileptic drugs.
However,ithasbeenshownthatmostanxiolyticagentsarealsoable
topreventorantagonizeMetrazolinducedconvulsions.
Procedure
Miceofeithersexwithabodyweightbetween18and22gareused.
The test compound or the reference drug is injected sc. or i.p. or
givenorallytogroupsof10mice.Anothergroupof10miceserves
ascontrol.Fifteenminaftersc.injection,30minafteri.p.injection,
or 60 min after oral administration 60 mg/kg MTZ (Metrazol) are
injected subcutaneously. Each animal is placed into an individual
plastic cage for observation lasting 1 h. Seizures and tonicclonic
convulsionsarerecorded.Atleast80%oftheanimalsinthecontrol
grouphavetoshowconvulsions.
ElectroShock(MES)InducedConvulsions
Principle
Theelectroshockassayinmiceisusedprimarilyasanindicationfor
compounds which are effective in grand mal epilepsy. Tonic hind
limbextensionsareevokedbyelectricstimuliwhicharesuppressed
byantiepilepticsbutalsobyothercentrallyactivedrugs(35).
Procedure
Themaximumelectricalshock(MES)inducedconvulsioninanimals
represented grand mal type of epilepsy. These are type of
proceduresusetostudiesconvulsionsandtotesttoanticonvulsant
drugs in laboratory animals. In MES convulsions electric shock is
applied through the corneal electrode, through optic stimulation
cortical excitation are produced .The MES convulsion are divided
into five phase such as Tonic flexion, Tonic extensor, Clonic
convulsions, stuper, recovery or death. A substance is known to
possess anticonvulsant property if it reduces or abolished the
extensorphaseofMESconvulsions.Thisproceduremaybeusedto
produceconvulsionsbothinratandinmice.
Inthismethodplacecornealelectrodesonthecorneaandapplythe
prescribedcurrentanddifferentstagesof conclusionsarenotedas
described in previous paragraph. Note the time (sec) spent by the
animalineachphaseoftheconclusions.Injectphenytoini.p.inrats.
Wait for 30 min and subject the animals to electroconvulsions as
described.Notethereductionintimeorabolitionoftonicextensor
phaseofMESconvulsions.

OtherMethods
Effectonpentobarbitalinducedsleepingtime
Rats were divided into groups [n=6] the group received dose of
anticonvulsants intraperitonealy, while the control group received
an equal volume of vehicle. After 10 min al animal received
50mg/kg(i.p.)ofpentobarbital.Thetimethatelapsedbetweenloss
of recovery of right reflex was taken as the seeping time and was
recordedbotharecontrolandpretreatedanimal
Motilitytest
For locomotor activity studies, mice receiving anticonvulsant drug
wereplacedingroupoffiveintherectangularcaseofactivitymeter
(U.Basil,Milano).Twogroupoffivemasseachwhereareeachdose
of anticonvulsant drug 127.5 and 255mg/kg and similar vehicle
13

treatedgroupareusedascontrols.activitycountarerecordedat10
minintervalsforperiodoftwohraftertreatment(36)resultsofthe
test substances with that of control at each time interval and
expressed as activity count of the test substances from that of
control.
Amphetaminetoxicitytest
Malealbinomiceweighing2530garedividedintofourgroupsof10
each.Theamphetaminetoxicitytestiscarriedoutasdescribed(37).
Briefly, control animals received intraperitonealy injection of the
vehicle (saline) while the test animals were injected with extract.
Both control and experimental animals received 5 mg/kg
amphetamine 30 min later and all mice are aggregated into cubic
cages with wire mesh sides. These cages are placed in noise
controlled room at 300C temperature for 5 hour. At the end of this
period,thenumberofmortalitywasnotedandrecorded.
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